The present invention relates to a novel compound having antimalarial activity and an antimalarial agent containing the novel compound as an active component.
Malaria is spread from person to person by the bite of a mosquito, Anopheles spp. A malaria parasite, being injected into a human body as a sporozoite together with saliva of a mosquito, enters into a hepatocyte and multiplies as an exoerythrocytic form (tissue form) parasite, and 10 to 14 days later, the parasite becomes a schizozoite and enters into the bloodstream to cause an infection, then multiplies through asexual reproduction wherein the parasite grows to a trophozoite, and to a schizont. A schizozoite, which corresponds to a seed of a plant, is produced in a mature schizont, and this schizozoite (merozoite) spills and enters into another erythrocyte, and then repeats its asexual reproduction. Although some of the schizozoites become male or female gametocytes without asexual reproduction, schizozoites cannot proliferate further in a human body, and schizozoites do not become male or female gametes and mate for sexual reproduction until they enter into the body of a mosquito. After several stages, such gamete matures and becomes a sporangium which has numerous sporozoites inside, and when a mosquito sucks the blood of human, such sporozoites are transfused into the human body together with saliva of the mosquito. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae, and it is estimated that 200 to 300 million people are infected with malaria in the world, and that two to three million people die from malaria every year. In recent years, there emerge insecticide-resistant mosquitoes and chloroquine-resistant malaria parasites, and it is becoming difficult to deal with these organisms.
As an antimalarial agent or an antimalarial compound, the following are conventionally known: a novel compound of ortho-condensation system containing two heterocycles as described in Japanese Laid-Open Patent Application No. 2000-7673; an antimalarial agent containing a compound having ICAM-1 expression suppressing activity as an active component as described in Japanese Laid-Open Patent Application No. 11-228446; an antimalarial agent containing a nucleoside derivative and the like such as 5xe2x80x2-o-sulfamoyl-2-chloroadenosine or the like as an active component as described in Japanese Laid-Open Patent Application No. 11-228422; an antimalarial agent containing tricothecenes and the like as an active component as described in Japanese Laid-Open Patent Application No. 11-228408; an antimalarial agent containing cycloprodigiosin and the like as an active component as described in Japanese Laid-Open Patent Application No. 10-265382; a drug for preventing or treating malaria containing riminophenazine as an active component as described in Japanese Laid-Open Patent Application No. 8-231401; an agent for overcoming antimalarial drug resistance containing a quinoline derivative and the like as an active component as described in Japanese Laid-Open Patent Application No. 8-73355; an antimalarial agent containing 5-fluoroorotic acid and sulfamonomethoxyne as an active component as described in Japanese Laid-Open Patent Application No. 8-59471; an antimalarial agent containing Astragalus membranaceus, Cinnamomum cassia, Rehmanniae Radix, Paeonia lactiflora, Cnidii Rhizoma, Atractylodis Lanceae Rhizoma, Angelicae Radix, Panax ginseng, Poria cocos and Glycyrrhizae Radix, or extracts thereof as an active component as described in Japanese Laid-Open Patent Application No. 7-82165; an antimalarial agent containing a tetrapyrrole derivative and the like as an active component as described in Japanese Laid-Open Patent Application No. 6-157308; an antimalarial agent containing 15-deoxyspergualin and the like as an active component as described in Japanese Laid-Open Patent Application No. 5-97665.
Malaria is a serious infection. 200 to 300 million people are infected with malaria and two to three million people die from malaria every year. Further, the emergence of a malaria parasite resistant to chloroquine, which is a drug heavily used as a panacea of malaria, has become a serious problem, and therefore, there is an urgent need to develop an effective remedy. Artemisinin, which is isolated from plants that belong to Asteraceae and has a trioxa structure, is effective to chloroquine-resistant malaria parasites, and this nature derived compound is currently used as a remedy. However, a malaria parasite which shows resistance also to artemisinin has already emerged as well, and it is causing a more serious problem. An object of the present invention is to provide a novel compound having antimalarial activity and an antimalarial agent containing the novel compound as an active component.
The inventors of the present invention have conducted intensive study as to synthesis of artemisinin analogues in order to attain the above-mentioned object, and found that 12-hidroxy-2-(1-methoxycarbonylethyl)-5-oxo-10,11,13-trioxatricyclo[7.2.0.01,6]tridecane synthesized by utilizing photooxidation reaction, from bicyclic olefin synthesized by intramolecular Diels-Alder reaction, shows extremely high antimalarial activity and selective toxicity, and the present invention has been thus completed.
The present invention relates to a compound represented by a following general formula (I) [wherein R1 represents a hydrogen atom or an optionally branched C1-C6 alkyl group, R2 represents a hydrogen atom, an optionally branched C1-C6 alkyl group or an optionally substituted aryl group, R3 represents an oxygen atom, a sulfur atom, NR4 (R4 represents a hydrogen atom or an optionally branched C1-C6 alkyl group) or CR52 (R5 each independently represents a hydrogen atom or an optionally branched C1-C6 alkyl group)](claim 1),
Chemical Formula 1
and the compound according to claim 1, wherein the compound represented by the general formula (1) is 12-hidroxy-2-(1-methoxycarbonylethyl)-5-oxo-10,11,13-trioxatricyclo[7.2.0.01,6]tridecane represented by a following formula (II) (claim 2).
Chemical Formula 2
The present invention further relates to an antimalarial agent containing a compound represented by a following general formula (I) [wherein R1 represents a hydrogen atom or an optionally branched C1-C6 alkyl group, R2 represents a hydrogen atom, an optionally branched C1-C6 alkyl group or an optionally substituted aryl group, R3 represents an oxygen atom, a sulfur atom, NR4 (R4 represents a hydrogen atom or an optionally branched C1-C6 alkyl group) or CR52 (R5 each independently represents a hydrogen atom or an optionally branched C1-C6 alkyl group)] as an active component (claim 3),
Chemical Formula 3
and the antimalarial agent according to claim 3, wherein the compound represented by the general formula (I) is 12-hidroxy-2-(1-methoxycarbonylethyl)-5-oxo-10,11,13-trioxatricyclo[7.2.0.01,6]tridecane represented by a following formula (II) (claim 4).
Chemical Formula 4
In the compound represented by the general formula (I) according to the present invention, R1 represents a hydrogen atom or an optionally branched C1-C6 alkyl group, and specific examples of such optionally branched C1-C6 alkyl group include a methyl group, an ethyl group, an isopropyl group and a t-butyl group. R2 represents a hydrogen atom, an optionally branched C1-C6 alkyl group or an optionally substituted aryl group, and specific examples of such optionally branched C1-C6 alkyl group include a methyl group, an ethyl group, an isopropyl group and a t-butyl group, and those of the optionally substituted aryl group include a phenyl group, a tolyl group and a naphthyl group, respectively. In addition, as a substituent in the aryl group, an optionally branched C1-C6 alkyl group, an optionally branched C1-C6 alkoxy group and the like are exemplified.
Further, in the compound represented by the general formula (I) according to the present invention, R3 represents an oxygen atom, a sulfur atom, NR4 (R4 represents a hydrogen atom or an optionally branched C1-C6 alkyl group) or CR52 (R5 each independently represents a hydrogen atom or an optionally branched C1-C6 alkyl group). As R4 in NR4, a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a t-butyl group and the like are specifically exemplified. Specific examples of R5 in CR52 include a hydrogen atom, a methyl group, an ethyl group, an isopropyl group and a t-butyl group. These two R5 may be same or different.
Among these compounds represented by the general formula (I), 12-hidroxy-2-(1-methoxycarbonylethyl)-5-oxo-10,11,13-trioxatricyclo[7.2.0.01,6]tridecane represented by the formula (II) having excellent antimalarial activity is preferable in view of antimalarial activity and selective toxicity.
A method of producing the compound represented by the general formula (I) according to the present invention and 12-hidroxy-2-(1-methoxycarbonylethyl)-5-oxo-10,11,13-trioxatricyclo[7.2.0.01,6]tridecane represented by the formula (II) is not particularly limited. For example, said compounds can be obtained as a peroxide moiety by a method comprising the steps of: triene is synthesized from 1,4-butanediol derivative by several steps of known synthetic reaction; the synthesized triene is stereoselectively transformed into cis-decalone through Dess-Martin oxidation followed by intramolecular Diels-Alder reaction; the cis-decalone is subjected to base treatment and then to singlet oxygen oxidation-air oxidation (Roth""s method).
When the compound according to the present invention is used for prevention, inhibition and treatment of infection caused by malaria parasites, any of oral administration, subcutaneous injection, intravenous injection, local administration or the like can be used as an administration route. As examples of drugs, drugs for oral administration such as powders, tablets, subtle granules, pills, capsules, granules or the like and those for parenteral administration such as instillations, injectable solutions, suppositories or the like, both formulated by using pharmaceutically acceptable carriers, excipients and other additives, are usually exemplified. Examples of pharmaceutically acceptable carriers, excipients and other additives include glucose, lactose, gelatin, mannitol, starch paste, magnesium trisilicate, corn starch, keratin, coloidal silica, and it may further contain adjuvants such as a stabilizer, an expander, a colorant and an aromatic substance. Each of these drugs can be produced by methods conventionally known to person skilled in the art. In addition, though the dose per day depends on symptom, weight, age, sex and the like of patients and cannot be determined uniformly, it is usually preferable to administer 0.1 to 1000 mg, more preferably 1 to 600 mg, of the compound according to the present invention per day to adult patients.
The present invention is explained below with reference to examples, but the technical scope of the present invention is not limited to these examples. Example 1 [Production of 12-hidroxy-2-(1-methoxycarbonyl-ethyl)-5-oxo-10,11,13-trioxatricyclo[7.2.0.01,6]tridecane] 12-hidroxy-2-(1-methoxycarbonylethyl)-5-oxo-10,11,13-trioxatricyclo[7.2.0.01,6]tridecane was synthesized by using (4E)-7-methyl-1-tetrahydropyranoxy-4,7-octadien-6-ol as a starting material. The starting material represented by a following formula (1), (4E)-7-methyl-1-tetrahydropyranoxy-4,7-octadien-6-ol was synthesized according to the method as previously described (the Journal of Organic Chemistry, Vol. 51, 4023-4028, 1986).
Chemical Formula 5